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Original Article Gastroenterology Research 2009;2(3)168-174

Effect of Zinc Supplementation in Children with Acute


Diarrhea: Randomized Double Blind Controlled Trial
Sangita S Trivedia, Rajesh K Chudasamab, c, Nehal Patela

Keywords: Acute diarrhea; Zinc; Placebo; Frequency of stool;


Abstract Randomized controlled trial; Blinding

Background: To test the hypothesis that daily supplementation


of zinc has any effect on clinical course of acute diarrhea, i.e. fre-
quency of stool, on stool amount and duration of acute diarrhea. Introduction

Methods: In a randomized double blind placebo controlled trial, Diarrheal disease constitutes a leading cause of mor-
117 children aged 6 months to 59 months in a medical college hos- bidity and mortality among children less than five years of
pital, with acute diarrhea of less than 14 days were assigned by age in developing countries [1]. In recent years, the major
permuted block design 1:1 to receive intervention of zinc supple- advance in the treatment of acute gastroenteritis in children
mented syrup (n = 60) or placebo syrup (n = 57). was the introduction of oral rehydration solution (ORS) in
the early stages of illness [2]. Significant proportions of chil-
Results: Baseline characteristics were similar in both the groups. dren who suffer from diarrhea are malnourished with deplet-
Mean age in zinc supplemented group was 22.14 16.68 months ed micronutrient stores. Diarrhea also leads to excess loss of
and in placebo group 25.66 17.02 months. Reduction in stool fre- micronutrients such as zinc and copper. Therefore children
quency per day was found 62% in zinc supplemented group and with marginal nutritional status are also at the greatest risk
26% reduction was found in placebo supplemented group with of developing zinc and copper depletion with an episode of
obvious difference of 36% between these two groups from day 1 diarrhea [3]. Zinc has direct effect on intestinal villus, brush
to day 3 and day 5, which was found statistically highly signifi- border disaccharidase activity and intestinal transport of wa-
cant. Similarly, significant difference was observed for reduction in ter and electrolytes [4]. Zinc supplements given during diar-
amount of stool per day from day 1 to day 3 and day 5 with obvious rhea reduce the duration and severity of treated episodes [5]
difference of 45% between the study groups. and, if given for total 14 days during and after diarrhea, can
reduce the incidence of diarrhea in subsequent two or three
Conclusions: Oral zinc administration in acute diarrhea reduces months [6]. Therefore, we conducted a randomized, double
the frequency of diarrhea and output of stool by changing the natu- blind, placebo controlled trial to test the hypothesis that daily
ral course of acute diarrheal disease, causes early normalization of supplementation of zinc has effect on frequency and amount
stool consistency, early recovery and decreases total duration of of stool and shortens the duration of acute diarrhea in chil-
hospital stay. Zinc supplementation is simple, acceptable and af- dren of 6 months to 5 years of age while treating acute diar-
fordable strategy which should be considered in management of rhea.
acute diarrhea.

Subjects and Methods

Manuscript accepted for publication June 12, 2009.


Study area and population enrollment
The study was conducted at pediatric department (single
a
Pediatric Department, Government Medical College, Surat, India centered), Government Medical College and Hospital, Surat,
b
Community Medicine Department, Government Medical College, Surat,
India
Gujarat, India as per the Helsinki Declaration and after ap-
c
Corresponding author: Shreeji Krupa, Meera Nagar, Street No.5, Raiya proval by the human research ethical committee of the Gov-
Road, Rajkot, Gujarat, India. E-mail address: dranakonda@yahoo.com, ernment Medical College, Surat. In present trial, all children
dranakonda@gmail.com
aged 6 months to 59 months who presented and admitted
doi:10.4021/gr2009.06.1298 to hospital (only inpatients) with more than three unformed

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Trivedi et al Gastroenterology Research 2009;2(3)168-174

stools in 24 hours and diarrheal duration of < 14 days were and this episode was considered terminated on the last day
eligible after written informed consent. All patients without of diarrhea followed by 24 hour diarrhea free period. The
any signs of dehydration were also monitored in diarrheal amount of stool was measured as primary outcome variable
treatment unit of the hospital. A child could be enrolled only from day of admission to day 5 or to the day of discharge.
once. Child with any other significant systemic illnesses The number and proportion of patients with diarrhea less
and severe malnutrition was excluded. Any child receiving than 14 days and mean length of hospital stay was also esti-
systemic or oral antibiotics, multivitamins, iron, antimotil- mated. Serum protein, albumin, alkaline phosphatase values
ity drugs, pre- and probiotics and other drugs before or after at the time of admission, impact of zinc supplementation on
admission were also excluded. stool amount during acute diarrhea were also estimated by
using biochemical investigation.
Baseline assessment
The following baseline data was collected, including Sample size and follow up
diarrheal duration, frequency of stool, amount of stool, char- A prospective study was conducted for one year, started
acter of stool (watery, mucoid or bloody), age, sex, maternal from August 1, 2007 to July 31, 2008. The purpose of select-
education, family income, diet of child (mostly breastfed, ing one year as study period was to cover all the seasons
partially breastfed, other milk, mixed feeding or family diet), throughout the year and avoid any selection bias and sea-
immunization status, history of fever or vomiting, prior use sonal influence. All patients having acute diarrhea in the age
of ORS, prior use of medications and nutritional status. All group of 6 months to 6 years admitted in hospital during this
patients with dehydration were provided oral rehydration so- period were enrolled in the study. Total 1492 pediatric pa-
lution as per WHO guidelines. Height and weight were mea- tients were admitted in wards of pediatric department during
sured by using UNICEF Detecto Scale by a trained person. this time period at Government Medical College, Surat. Out
Infantometer was used to measure length of children below of these, 196 admission were belongs to 6 months to 5 years
24 months of age. Stool output was monitored as soon as of age group with diarrhea. Total 117 patients were enrolled
patient was admitted, and weighed as and when required by in this study out of 196 admissions of study group through-
using electronic weighing machine during hospitalization by out the year. Remaining 79 patients in same age group were
trained personnel. All the information was recorded on pre- excluded because they were having concomitant other ill-
designed and pretested proforma. ness, received some systematic or oral antibiotic before ad-
mission or any kind of other drugs, received preadmission
Interventions multivitamins/iron, antimotility drugs, pre and probiotics
The liquid preparation containing zinc or a placebo like lactobacilli, etc. Parents of all 117 patients have given
used as syrup in present trial contained (1) water and sugar at written consent and were enrolled in this study without re-
50% concentration, (2) mix fruit flavored agent, and (3) Na fusal to participate, of which 60 patients were allocated to
Benzoate (0.2%) as a preservative. The zinc syrup contains experimental group and 57 patients to placebo group after
same vehicle with zinc sulfate with concentration of 2 mg randomization. They were followed up in hospital after ad-
elemental zinc per milliliter (ml). Both the syrup bottles con- mission on day 1, 3, and 5. At the end of follow up after 5
taining either zinc or a placebo were identical in appearance days in the hospitalized patients, 44 patients were remained
and taste. Syrup bottles were given to each childs mother in experimental group and 44 patients in placebo group and
and kept with them. Patients were given double the recom- included in analysis.
mended daily allowance of zinc, as 5 ml (10 mg) for child
less than one year and 10 ml (20 mg) for child more than one Randomization sequence generation, allocation con-
year in two divided doses per day after hospital admission, cealment and implementation
and continued till they were get cured and discharged. Children who fulfilled the inclusion criteria were en-
rolled into two treatment groups, experimental and placebo
Objectives group. The sequence to enroll children in either group was
Present trial was done to test the hypothesis that daily generated by using restricted randomization by using per-
supplementation of zinc have any effect on clinical course muted block design of 1:1 to ensure that the comparison
of acute diarrhea, frequency of stool, on stool amount and groups will be of approximately equal size. Stratification
duration of acute diarrhea in children age group 6 months to was done as per the age, and socioeconomic status of chil-
5 years of age. dren. Age was grouped in 6 - 12 months, 13 - 36 months and
37 - 60 months groups. Modified Prasads socioeconomic
Outcome variables classification [7] was used to determine socioeconomic sta-
The primary outcome was frequency of diarrhea per tus of children. Patients were allocated a specific numbered
day from the time of onset. A diarrhea was considered as a bottle of either zinc or placebo syrup without revealing its
24 hour period with passage of at least three unformed stools identity. The person who made the sequence generation was

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Zinc Supplementation in Acute Diarrhea Gastroenterology Research 2009;2(3)168-174

Figure 1. Flow diagram of a trial of zinc supplementation in children with acute diarrhea. * LAMA- Leave
against medical advice

not monitoring the study groups. The sequence code num- All study participants and personnel including care provid-
bers were kept in a sealed envelop with one of the senior of- ers, evaluators and monitors were blinded to treatment as-
ficer who identified the groups after completion of the study. signment for the whole duration of the study to avoid any
After recovery from illness, children were discharged and type of bias. Patient blinding was evaluated by asking ques-
parents were advised to continue the given syrup for total 14 tions to patients and their parents to indicate which type of
days along with home available routine diet. Due care was treatment they believed they had received like special medi-
taken to provide adequate amount of appropriate bottle of cine containing syrup or a routine syrup during follow up on
zinc/placebo syrup at discharge of patients. day 3, day 5 or at time of discharge if earlier. But no patient
replied that they have any idea about the type of syrup they
Blinding are receiving. Similarly, blinding study personnel including
Double blinding technique was used in present study. care providers were asked questions that which type of syrup

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Trivedi et al Gastroenterology Research 2009;2(3)168-174

Table 1. Baseline characteristics of zinc supplemented and placebo group children

Zinc supplemented group Placebo group


(n = 44) (n = 44)
Variables
No. % No. %

Age in months
6 - 12 19 43.2 17 38.6
13 - 36 18 40.9 18 40.9
37 - 60 7 15.9 9 20.5

Sex of child
Male 23 52.3 16 36.4
Female 21 47.7 28 63.6

Socioeconomic status
Upper 12 27.3 20 45.5
Middle 18 40.9 14 31.8
Lower 14 31.8 10 22.7

Diarrhea frequency/day on
admission
4 9.1 2 4.5
5
8 18.2 13 29.6
6 - 10
32 72.7 29 65.9
> 10

No. of days for diarrhea on


admission
41 93.2 41 93.2
7
3 6.8 3 6.8
8 - 14

Diarrhea with fever


Yes 18 40.9 15 34.1
No 26 59.1 29 65.9

Diarrhea with vomiting


Yes 36 81.8 36 81.8
No 8 18.2 8 18.2

they believed that they are giving to the patients. When they compared and analyzed by using Epi Info 6 software. Mean
answered either zinc or placebo syrup, they were asked to and standard deviations (SD) were calculated and statistical
indicate how they have identified, but no one has correctly significance was tested by using Students t test. Two sided
identified. significance tests were used throughout.

Statistical analysis
All data analysis was done as per the preestablished Results
analysis plan. Exploratory data analysis was carried out to
assess the distribution of study variables. Baseline char- Flow and follow up of participants
acteristics of treatment groups were entered in computers, Total 1492 patients were admitted to pediatric depart-

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Zinc Supplementation in Acute Diarrhea Gastroenterology Research 2009;2(3)168-174

ment at Government Medical College, Surat during study served from day 1 to day 3 and day 5 while comparing zinc
period. Out of these, 196 patients belonged to study group supplemented group and placebo group. Serum protein, al-
(Fig. 1). Due to exclusion criteria, 79 children were excluded bumin, and alkaline phosphatase, and zinc were also checked
from the trial. So, 117 children were allocated for the trial. in all the age groups by doing biochemical investigations.
Among these, 60 were allocated in experimental group re- Serum alkaline phosphatase was found low in study groups.
ceiving zinc syrup and 57 were allocated in placebo group Serum zinc level was found low at time of admission but
receiving placebo syrup. During hospital follow up, 16 pa- on third day when tested again, shown rise in serum level
tients were lost to follow up in experimental group and 13 in in zinc supplemented group. Body weight and mid arm cir-
placebo group as they left hospital against medical advice. cumference measurement at time of admission and at time
Finally, 44 patients were remained for analysis in both the of discharge was done but was statistically not significant.
groups. Mean age in zinc supplemented group was 22.14 Compliance of every enrolled patient was found adequate
16.68 months and in placebo group 25.66 17.02 months. throughout the study. All patients were observed for any kind
of adverse effects during trial by monitoring each patient by
Analysis examining and by asking patients for any adverse effect de-
Baseline characteristics of study group children are velopment but no adverse effects were reported in any of the
shown in Table 1. Majority participants belong to age 6 study participants throughout the trial.
months to 36 months. There was an almost equal socioeco-
nomic distribution among study participants. Diarrhea fre-
quency more than 10 times per day with less then 7 days du- Discussion
ration on admission was found mainly in both study groups.
Table 2 shows impact of zinc supplementation on fre- Present study examined several aspects of zinc supple-
quency of stool per day during follow up on day 1, day 3 mentation. Our study data indicates that supplementing the
and day 5 during acute diarrhea. Results showed that in all children with acute watery diarrhea in age group of 6 - 60
the age groups, stool frequency per day significantly reduced months with double the recommended daily intake of zinc
from day 1 to day 3 and day 5 in zinc supplemented group during the period of acute illness has significantly decreased
compare to placebo group, which was primary outcome vari- the frequency of diarrhea and amount of stool output, and
able. Reduction in stool frequency per day was found 62% improved the early normalization of stool consistency on
in zinc syrup supplemented group and 26% reduction was third day of zinc supplementation. Considering the recov-
found in placebo syrup supplemented group with obvious ery parameters, it is acknowledged that stool output has
difference of 36% between these two groups (p < 0.01). decreased significantly in total patients supplemented with
Effect of zinc supplementation on stool amount per day zinc (p < 0.05) on day 3 and day 5 as compared to control
is shown in Table 3. All the stool evacuations were collected placebo group. Present study also showed significant reduc-
and weighed by trained personnel in hospital. Significant re- tion in stool frequency (36%) and in stool output (45%) by
duction in per day stool amount as primary outcome was ob- zinc supplementation on third day. The findings of present

Table 2. Impact of zinc supplementation on frequency of stool per day during follow up as per mean SD

Zinc supplementation Placebo group


Age group group (n = 44) (n = 44)

Day 1 Day 3 Day 5 Day 1 Day 3 Day 5

6-12 9.05 4.89 3.75 2.59* 2.90 1.92* 11.19 7.21 8.57 7.78 3.4 3.53*

13-36 11.78 7.25 3.89 2.91* 1.92 1.32* 11.89 9.64 8.37 6.39 3.54 3.47*

37-60 8.28 7.25 5.4 3.43 1.91 1.21* 7.77 2.10 6.5 1.92 3.59 3.43

Total 10.7 6.38 4.06 2.82* 2.32 1.58* 10.86 7.71 8.05 6.26 3.40 3.34*

* Indicates p < 0.01, percent reduction in frequency of stool/day- Zinc: 62%, Placebo: 26%, difference: 36%.

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Trivedi et al Gastroenterology Research 2009;2(3)168-174

Table 3. Impact of zinc supplementation on amount of stool/day during management of acute diarrhea as per
mean SD

Zinc supplementation Placebo group


group (n = 44) (n = 44)
Age group
Day 1 Day 3 Day 5 Day 1 Day 3 Day 5

6-12 161.8 195.5 116.4 18.8 43.8 31.9* 164.7 182.4 226.7 419.5 158.0 239.0

13-36 345.5 296.2 181.1 220 103.3 78.1* 232.7 273.2 195.1 187.4 139.7 147.9

37-60 261.0 232.0 77 54.3 113.3 118.4 68.7 46.1 38.6 51.8 131.2 163.5

Total 259.6 272.2 144.4 175* 80.7 72.8* 173.4 215.9 183.9 292.9 148.8 192.3

*Indicates p <0.05, percent reduction in stool output/day, Zinc: 45%, Placebo: 0%, difference: 45%.

study indicate that zinc supplementation in acute diarrhea ef- suggested as an important surrogate marker of zinc status in
fectively reduces both frequency of diarrhea and output of human [14]. In present study, it has been shown that serum
stool. Baqui AH et al [8] reported in their study of zinc and alkaline phosphatase was low in all patients, may be corre-
copper supplementation on Bangladeshi children, that those lating with zinc deficiency, but we were not able to do the
who received zinc supplementation during and after diarrhea follow up study on the seventh and fourteenth day supple-
had 24% shorter duration of diarrhea, 15% lower incidence mentation. This is the limitation of our study that rise in se-
of diarrhea, and a trend suggesting fewer diarrhea related rum alkaline phosphatase with serial zinc supplementation
hospital admissions. was not followed as supported by other studies [15]. But as
Moreover, the diarrheal duration and frequency, pri- we have measured serum zinc on third day of supplementa-
mary concerns of the mother also do provide some valuable tion with zinc syrup, it was seen that serum zinc has shown
information regarding recovery. As is seen that the diarrhe- significant rise on third day, that suggests that sufficient ab-
al frequency and duration was comparable in both groups sorption and replenishment of body zinc occurred with the
initially, but on third day the zinc supplemented group has double dose of zinc used. Both the groups were not given
shown faster recovery in frequency and duration of diarrhea. any other multivitamin or micronutrient supplement which
In contrast, Patel AB et al [3] have reported that most im- may interfere with absorption of others and study results by
portant predictor for duration of diarrhea in children was the their effect.
severity of the disease at enrollment, and not the supplemen- Present study was hospital based and only admitted pa-
tation, but in contrast present study showed no such role of tients to the pediatric wards were enrolled in the study which
disease severity. The reduction in duration of diarrhea epi- leads to selection bias, excluding patients treated on outpa-
sode is consistent with earlier studies [9, 10]. A meta-analy- tient and that was the limitation of present study.
sis of five studies of zinc treatment for acute diarrhea found In conclusion, oral zinc administration in acute diarrhea
a summary estimate for reduction in duration of 16% [5]. decreases the frequency of diarrhea and output of stool by
Possible mechanisms for the effect of zinc treatment on the changing the natural course of acute diarrheal disease, causes
duration of diarrhea include improved absorption of water early normalization of stool consistency, early recovery and
and electrolytes by intestine, faster generation of gut epithe- decreases total duration of hospital stay. Zinc supplemen-
lium, enhanced immune response, leading to early clearance tation is simple, acceptable and affordable strategy which
of diarrheal pathogens from intestine [11, 12]. Rahman MM should be considered in management of acute diarrhea.
et al [13] have reported that combined zinc and vitamin A
synergistically reduced the prevalence of persistent diarrhea
and dysentery. Acknowledgements
Serum alkaline phosphatase measurement has been

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The authors declare no conflicts of interest related to veloping countries: pooled analysis of randomized con-
this article. Authors are thankful to all participants of study trolled trials. Zinc Investigators Collaborative Group. J
for their participation and nursing personnel of pediatric de- Pediatr 1999;135(6):689-697.
partment for their valuable support. 7. Singhania VK. Students guide to income tax 2001-02, p.
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study, its coordination, helped in statistical analysis and 8. Baqui AH, Black RE, Arifeen SE, Yunus M, Chakraborty
manuscript drafting. NP supervised the data collection and J, Ahmed S, et al. Effect of zinc supplementation started
helped in statistical analysis. RKC participated in its design during diarrhea on morbidity and mortality in Bangla-
and coordination, statistical analysis and manuscript prepa- deshi children: community randomized trial. BMJ 2002;
ration. All authors read and approved the final manuscript. 325: 1-7.
9. Sazawal S, Black RE, Bhan MK, Bhandari N, Sinha A,
Jalla S. Zinc supplementation in young children with
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